神经系统副肿瘤综合征临床分析

目的 了解神经系统副肿瘤综合征患者的临床特点.方法 收集我院收治的神经系统副肿瘤综合征患者28例,对其临床资料进行回顾性分析.结果 患者多为慢性隐袭或亚急性起病,进行性加重,治疗后无明显缓解,3.8%患者在发现肿瘤后才出现神经症状;96.2%在出现副肿瘤症状后才发现肿瘤,副肿瘤综合征的临床类型有Lambert-Eaton肌无力综合征8例、周围神经病7例、多发性肌炎和皮肌炎4例、脑干脑炎3例、进行性小脑变性2例、边缘系统脑炎2例、运动神经元病1例、进行性多灶性白质脑病1例.结论 神经系统副肿瘤综合征临床表现形式多样,容易误诊,临床早期确诊对于隐匿肿瘤的发现和治疗非常重要.     

神经系统副肿瘤综合征24例临床分析

目的了解神经系统副肿瘤综合征的临床特点。方法回顾性分析24例神经系统副肿瘤综合征患者的临床资料并进行总结。结果 24例神经系统副肿瘤综合征患者平均年龄68.7岁,男女比例为1∶0.7。神经系统表现为边缘叶脑炎、亚急性小脑变性、脑干脑炎、周围神经病、Lambert-Eaton肌无力综合征和恶病质肌病。肿瘤来源以肺癌为主,占79.1%。75%的病例先于肿瘤表现出PNS的症状。结论 PNS表现多样,早期识别症状对于诊治PNS、发现肿瘤非常重要。     

神经系统副肿瘤综合征16例临床分析

目的:对神经系统副肿瘤综合征的临床特点进行分析,探讨可能的病因。方法:对16例神经系统副肿瘤综合征患者进行回顾性分析。结果:本组临床类型有:肌无力综合症9例,周围神经病5例,脑干脑炎1例,亚急性小脑变性1例。肿瘤类型多样,以小细胞肺癌多见、其它有乳腺癌、淋巴瘤、胃癌、食管癌。结论:神经副肿瘤综合征的临床表现多种多样,最早在肿瘤确诊前1.5年出现,免疫机制异常可能在发病中起重要作用。     

多重抗神经元抗体阳性的神经系统副肿瘤综合征临床分析

目的探讨神经系统副肿瘤综合征患者出现多重抗神经元抗体的临床特征及潜在意义。方法检索2015年7月至2019年12月至宣武医院住院治疗并诊断为"神经系统副肿瘤综合征""癌性副肿瘤综合征""副肿瘤相关性周围神经病""边缘性脑炎"及"自身免疫性脑炎"的患者,筛选出两种或两种以上抗神经元抗体均为阳性的患者。结果在134例符合诊断的患者中,6例存在多重抗神经元抗体,包括抗Amphiphysin抗体合并抗γ-氨基丁酸受体B型(GABA_BR)抗体阳性2例[其中1例抗Hu抗体及抗谷氨酸脱羧酶(GAD65)抗体亦呈阳性],以及抗SOX1抗体合并抗Titin抗体阳性、抗Yo抗体合并抗富亮氨酸胶质瘤失活蛋白1(LGI1)抗体阳性、抗接触蛋白相关蛋白2(CASPR2)抗体合并抗LGI1抗体阳性和抗Hu抗体合并抗Ri抗体阳性各1例。6例患者临床表现均符合副肿瘤综合征,4例为周围神经病或肌肉接头病(其中2例合并边缘性脑炎,1例合并亚急性小脑变性),另2例单纯表现为边缘性脑炎;2例对免疫治疗有效;3例明确诊断癌症,分别为乳腺癌、胆管癌、小细胞肺癌。结论多重抗神经元抗体的存在,可导致患者的临床表现复杂多样,免疫治疗可能有效。存在某种抗神经元抗体的患者即使无相应神经综合征,该抗体亦对恶性肿瘤有提示意义。     

副癌神经综合征15例临床分析

目的 提高对副癌神经综合征临床特点的认识。方法 对15例副癌神经综合征患者的临床资料进行回顾性分析。结果 本组副癌神经综合征患者均亚急性，慢性起病，13例以神经系统症状首发。周围神经病8例，小脑变性3例，Ewaton-Lambert综合征2例，运动神经元病1例，多发性肌炎1例。原发肿瘤常见于肺癌，淋巴瘤，乳腺癌和生殖器肿瘤，常规检查难以早期诊断，治疗原发肿瘤和免疫抑制剂治疗可改善神经症状。结论 副癌神经综合征大多先天肿瘤复发，影响神经系统各中位，临床症状复杂，预后较差。     

神经系统副肿瘤综合征11例临床分析

目的　对神经系统副肿瘤综合征 (Neurologicalparaneoplasticsyndrome ,NPS)的临床特点进行分析 ,探讨可能的病因与早期诊断。方法　对 11例神经系统副肿瘤综合征患者临床资料进行回顾性分析。结果　癌性肌病 6例 ,癌性周围神经病 2例 ,低血糖昏迷 2例 ,亚急性小脑变性 1例。癌肿部位 :肺癌 5例 ,肝癌 2例 ,乳腺癌 2例 ,淋巴瘤 1例 ,前列腺癌 1例。结论　神经系统副肿瘤综合征临床表现形式多样 ,可由多种病因引起 ,只有提高对本病的认识 ,才能早期诊断 ,合理治疗。     

神经系统副肿瘤综合征11例临床分析

目的 对神经系统副肿瘤综合征（Neurological paraneoplastic syndrome,NPS)的临床特点进行分析，探讨可能的病因与早期诊断。方法：对11例神经系统副肿瘤综合征患者临床资料进行回顾性分析。结果：癌性肌病6例，癌性周围神经病2例，低血糖昏迷2例，亚急性小脑变性1例，癌肿部位：肺癌5例，肝癌2例，乳腺癌2例，淋巴瘤1例，前列腺癌1例，结论：神经系统副肿瘤综合征临床表现形式多样，可由多种病因引起，只有提高对本病的认识，才能早期诊断，合理治疗。     

副癌神经综合征20例临床分析

目的　提高对副癌神经综合征的临床特点的认识 ,减少误诊误治率。方法　对 2 0例副癌神经综合征患者的临床资料进行回顾性分析。结果　本组副癌神经综合征患者均亚急性、慢性起病 ,15例以神经系统症状为首发。周围神经病 8例 ,脊髓病 2例 ,小脑变性 3例 ,肌无力综合征 5例 ,多发性肌炎 2例。原发肿瘤常见于支气管肺癌、淋巴瘤、乳腺癌和卵巢癌 ,常规检查难以早期诊断 ,治疗原发肿瘤和免疫抑制剂可改善神经症状。结论　副癌神经综合征大多先于肿瘤发病 ,影响神经系统各部位 ,临床症状复杂 ,预后较差。     

副癌神经综合征20例临床分析

目的．提高对副癌神经综合征的临床特点的认识，减少误诊误治率。方法 对20例副癌神经综合征患者的临床资料进行回顾性分析，结果：本组副癌神经综合征患者均亚急性，慢性起病，15例以神经系统症状为首发，周围神经病8例，脊髓病2例，小脑变性3例，肌无力综合征5例，多发性肌炎2例。原发肿瘤常见于支气管肺癌，淋巴瘤，乳腺癌和卵巢癌，常规检查难以早期诊断，治疗原发肿瘤和免疫抑制剂可改善神经症状，结论：副癌神经综合征大多先于肿瘤发病，影响神经系统各部位，临床症状复杂，预后较差。     

14例抗Hu抗体阳性神经系统副肿瘤综合征临床特征分析

目的 探讨抗Hu抗体阳性神经系统副肿瘤综合征(PNS)的临床特征。方法 收集2016年1月至2020年9月郑州大学第一附属医院收治的抗Hu抗体阳性的确诊PNS的患者,均依据2021年副肿瘤综合征更新诊断标准及PNS诊断评分系统(PNS-Care Score)进行诊断。患者均随访至2021年8月,分析其临床表现、治疗及预后。结果 共收入14例PNS患者,男8例、女6例,年龄42～74岁,平均(58.93±9.50)岁。14例PNS患者中表现为周围神经病9例(64.3%),其中7例(50.0%)为感觉运动神经病、2例(14.3%)为感觉神经元病,表现为边缘性脑炎和快速进展性小脑综合征各2例(14.3%)、脑干脑炎1例(7.1%);合并小细胞肺癌11例(78.6%),乳腺癌、胸腺瘤及B细胞淋巴瘤各1例(7.1%)。14例中11例(78.6%)在肿瘤确诊之前出现神经系统症状,延迟诊断15 d至14个月,中位延迟时间为4.00(2.00,6.00)个月。14例PNS患者中,8例接受肿瘤治疗,8例接受免疫治疗,其中甲泼尼龙冲击6例、丙种球蛋白治疗2例,3例仅接受对症治疗;3例病情好转,11例死亡。...     

Intravenous immunoglobulins in the therapy of paraneoplastic neurological disorders

The treatment of paraneoplastic neurological syndromes (e.g., tumor therapy, immunosuppressive therapy, plasmapheresis) rarely leads to an improvement in the neurological symptoms. We treated four patients suffering from paraneoplastic neurological syndromes with intravenous immunoglobulins. All four had high titers of antineuronal antibodies in serum and CSF. Two of the patients, one suffering from paraneoplastic cerebellar degeneration and the other from paraneoplastic brain stem encephalitis and polyneuropathy, received intravenous immunoglobulin treatment within 3 weeks of the onset of neurological symptoms. Both patients showed clinical improvement within 2 weeks after the initiation of therapy. They also showed a decline in the intrathecal antibody synthesis of the antineuronal antibody. Two other patients, who had suffered from paraneoplastic neuropathy for 3 and 6 months showed no improvement with the intravenous immunoglobulin therapy. In these cases there was no effect on intrathecal antibody synthesis. When started early, intravenous immunoglobulins may be of therapeutical value in treating paraneoplastic neurological syndromes. Specific intrathecal antibody synthesis may be a better measure of clinical course that autoantibody serum titers. Received: 25 March 1998 Received in revised form: 11 August 1998 Accepted: 28 August 1998     

Complicated paraneoplastic neurological syndromes: a report of two patients with small cell or non-small cell lung cancer

Paraneoplastic neurological syndromes are frequently associated in patients with small cell lung cancer (SCLC) and antineuronal antibodies are involved in the autoimmune mechanism. Multiple syndromes are sometimes complicated in a single patient with SCLC. However, little is known about non-SCLC-associated neurological manifestations. We report two patients with complicated paraneoplastic neurological syndromes. Patient 1 showed paraneoplastic limbic encephalitis (PLE), paraneoplastic sensory neuropathy (PSN) and Lambert-Eaton myasthenic syndrome (LEMS) associated with SCLC. Patient 2 developed opsoclonus-ataxia and probable PLE associated with non-SCLC. Analysis of various antineuronal antibodies revealed that anti-Hu and P/Q-type voltage-gated calcium channel (VGCC) antibodies were positive in Patient 1 but any antibodies were not in Patient 2. Brain MRI demonstrated high intensity signals in temporal lobes particularly on fluid-attenuated inversion recovery (FLAIR) or diffusion-weighted images. These findings suggest that complicated paraneoplastic neurological syndromes occur in non-SCLC as well as SCLC and that unidentified antineuronal autoantibodies may underlie the pathophysiology.     

Antiamphiphysin antibodies are associated with various paraneoplastic neurological syndromes and tumors

BACKGROUND: Antiamphiphysin antibodies react with a 128-kd protein found in synaptic vesicles.They were first described in patients with paraneoplastic stiff-man syndrome and breast cancer, but studies suggest that they can also occur in patients with other tumors and neurological disorders. OBJECTIVE: To determine if antiamphiphysin antibodies are associated with various paraneoplastic neurological syndromes and tumors. PATIENTS AND METHODS: Of 2800 serum samples tested by routine immunohistochemical procedures on sections of paraformaldehyde-fixed rat brain for the detection of autoantibodies associated with paraneoplastic neurological syndromes, 5 were selected because of labeling suggestive of antiamphiphysin antibodies and subsequently confirmed by the results of Western blot analysis using recombinant amphiphysin protein. Controls consisted of 40 patients with various nonparaneoplastic neurological diseases; 101 patients with cancer but without paraneoplastic neurological syndrome; 9 patients with small cell lung cancer, anti-Hu antibodies, and paraneoplastic neurological syndrome; 3 patients with M2-type antimitochondrial antibodies but no neurological disorder; and 30 normal subjects. RESULTS: Of the 5 patients with antiamphiphysin antibodies, patient 1 had sensory neuronopathy, encephalomyelitis, and breast cancer; patient 2 had limbic encephalitis, and small cell lung cancer was detected in the mediastinum after 24 months of follow-up; patient 3 had encephalomyelitis and ovarian carcinoma; and patients 4 and 5 had Lambert-Eaton myasthenic syndrome and small cell lung cancer (patient 4 subsequently developed cerebellar degeneration). None of the 5 had stiffness. Two patients (Nos. 2 and 4) had antimitochondrial antibodies. The two patients (Nos. 4 and 5) with Lambert-Eaton myasthenic syndrome had antibodies directed against the voltage-gated calcium channel, and patient 2 subsequently developed anti-Hu antibodies. In the controls, antiamphiphysin antibodies were detected by Western blot analysis in 3 of 8 patients with anti-Hu antibodies, but in none of the other groups. CONCLUSIONS: These data indicate that antiamphiphysin antibodies are not specific for one type of tumor or one neurological syndrome and can be associated with other neural and nonneural antibodies. The simultaneous association of several antibodies in some patients suggests multimodal autoantibody production.     

Anti-neuronal antibodies and central nervous system diseases: contribution to diagnosis and pathophysiology

Antibodies against antigens found in the central nervous system have been evidenced in several neurological diseases. The most well-known are associated with paraneoplastic neurological diseases (Anti-Hu, Yo, Ri amphiphysin, Tr, CV2 and Ta antibodies). Some of these antibodies are specific for certain types of cancer or neurological syndromes and are highly useful diagnostic tools for the clinician. They have contributed to the hypothesis that these paraneoplastic neurological syndromes involve autoimmune cross reactions between tumoral and nervous system antigens. They are however most unlikely pathogenic on their own. Anti voltage-dependent calcium channel antibodies associated with Lambert-Eaton syndrome which is paraneoplastic in only 60 p. 100 of the cases are also observed in cases of paraneoplastic cerebellar atrophy. Anti-GAD antibodies are seen in non-paraneoplastic stiff man syndrome and in certain progressive cerebellar atrophies. Antibodies reacting with different glutamate receptors are detected in different neurological diseases including Rasmussen's encephalitis. Finally, antibodies are described in diverse conditions such as amyotrophic lateral sclerosis, Sydeham chorea or Gilles de la Tourette syndrome. The significance of the antibodies observed outside the context of paraneoplastic syndromes is not well understood, but the anti-GAD antibodies associated with progressive cerebellar disorders and autoimmune polyendocrinopathies could be an expression of the autoimmune nature of certain neurological degenerative processes affecting the central nervous system.     

BR serine/threonine kinase 2: a new autoantigen in paraneoplastic limbic encephalitis

We describe a new antigen, BR serine/threonine kinase 2 (BRSK2), identified by an antibody present in the serum of a patient with limbic encephalitis and small-cell lung cancer (SCLC). Patient's serum immunolabeled the neuronal cytoplasm and, less intense, the neuropil of rat brain but did not immunoreact with other rat tissues with the exception of testis. Immunoblots of rat brain homogenate identified several immunoreactive bands in the range of 88-82 kDa and a weaker broad band of 47-43 kDa. Probing a rat hippocampus expression library with the patient's serum resulted in the isolation of BR serine/threonine kinase 2 (BRSK2), a protein (also know as SAD1B kinase) preferentially expressed in the brain and testis and implicated in neuronal polarization as well as synaptic development. Eluted IgG from the BRSK2 clone gave a similar immunolabeling than the patient's serum by immunohistochemistry and immunoblot of rat brain and testis. BRSK2 antibodies reacted with two SCLC from patients without paraneoplastic neurological syndromes. No anti-BRSK2 antibodies were found in the serum of 50 patients with SCLC without PNS, 19 with limbic encephalitis without onconeural antibodies, 50 with anti-Hu antibodies and several paraneoplastic neurological syndromes, including 14 with limbic encephalitis, and 160 with a variety of non-paraneoplastic neurological syndromes. Our study suggests BRSK2 may be an autoantigen involved in the pathogenesis of SCLC-associated limbic encephalitis.     

Paraneoplastic neurological syndromes

PURPOSE OF REVIEW: This review discusses recent advances and current controversies in the aetiology, investigation and management of paraneoplastic neurological syndromes. RECENT FINDINGS: Antibody studies continue to define potential target autoantigens in paraneoplastic neurological syndromes and although pathogenic activity has been demonstrated for anti-glutamate receptor antibodies identified in a subset of patients with cerebellar ataxia, a role for paraneoplastic antibodies in the development of neuronal dysfunction has not been established in the majority of cases. As a result, attention has turned towards clarifying the role of adaptive cellular immunity in the pathogenesis of paraneoplastic neurological syndromes and several studies have defined expanded populations of cytotoxic T lymphocytes specific for epitopes derived from neuronal antigens in patients with paraneoplastic neurological syndromes. In vitro studies demonstrate the potential for antigen-specific cytotoxic T lymphocytes to restrict tumour growth and metastasis, but further investigation is needed to identify the mechanisms by which cytotoxic T lymphocytes could induce neuronal death. Clinical studies have demonstrated that effective tumour treatment can in some instances lead to improvement or stabilization of neurological symptoms. This is an encouraging observation since increased numbers of diagnostic paraneoplastic antibodies can now be reliably tested for and the use of [18F] fluoro-2-deoxyglucose positron emission tomography can facilitate earlier tumour diagnosis in patients presenting with paraneoplastic neurological syndromes. SUMMARY: Advances in the clinical management of patients with paraneoplastic neurological syndromes have occurred despite the fact that in most cases the immune effector mechanisms that lead to the development of neurological dysfunction remain to be characterized.     

Antibodies and neuronal autoimmune disorders of the CNS

We review the neuronal antibodies described in CNS disorders in order to clarify their diagnostic value, emphasize potentials pitfalls and limitations in the diagnosis of paraneoplastic neurological syndromes (PNS), and examine the current evidence for a possible pathogenic role. We propose to classify the neuronal antibodies associated with syndromes resulting from CNS neuronal dysfunction into two groups according to the location of the antigen: inside the neuron or in the cell membrane. Group I includes antibodies which target intracellular antigens and probably are not pathogenic. They are further subdivided into three groups. Group Ia comprises well-characterized onconeural antibodies (Hu (ANNA1), Yo (PCA1), Ri (ANNA2), CV2 (CRMP5), amphiphysin, Ma2) that are useful for the diagnosis of PNS. Group Ib antibodies (SOX and ZIC) are cancer-specific but there is no evidence that the immune response is in any way pathogenically related to the PNS. Antibodies in group Ic (glutamic acid decarboxylase (GAD), adenylate kinase 5 and Homer 3) identify non-PNS: stiff-person syndrome (SPS), cerebellar ataxia, and limbic encephalitis (LE). Group II antibodies recognize neuronal surface antigens. Antibodies in group IIa associate with characteristic CNS syndromes but their detection does not indicate that the disorder is paraneoplastic. Antibodies to potassium channels, AMPA and GABA_B receptors are associated with LE, NMDA receptor antibodies identify a well-defined encephalitis, and antibodies against glycine receptors associate with SPS with encephalitis. A pathogenic role of the antibodies is suggested by the response of symptoms to immunotherapy and the correlation between antibody titers and neurological outcome. Lastly, Group IIb includes antibodies that are found in patients with paraneoplastic cerebellar ataxia associated with lung cancer (P/Q type calcium channels antibodies) or Hodgkin disease (metabotropic glutamate receptor type 1 antibodies).     

Management of paraneoplastic neurological syndromes: report of an EFNS Task Force

Paraneoplastic neurological syndromes (PNS) are remote effects of cancer on the nervous system. An overview of the management of classical PNS, i.e. paraneoplastic limbic encephalitis, subacute sensory neuronopathy, paraneoplastic cerebellar degeneration, paraneoplastic opsoclonus-myoclonus, Lambert–Eaton myasthenic syndrome and paraneoplastic peripheral nerve hyperexcitability is given. Myasthenia gravis and paraproteinemic neuropathies are not included in this report. No evidence-based recommendations were possible, but good practice points were agreed by consensus. Urgent investigation is indicated, especially in central nervous system (CNS) syndromes, to allow tumour therapy to be started early and prevent progressive neuronal death and irreversible disability. Onconeural antibodies are of great importance in the investigation of PNS and can be used to focus tumour search. PDG-PET is useful if the initial radiological tumour screen is negative. Early detection and treatment of the tumour is the approach that seems to offer the greatest chance for PNS stabilization. Immune therapy usually has no or modest effect on the CNS syndromes, whereas such therapy is beneficial for PNS affecting the neuromuscular junction. Symptomatic therapy should be offered to all patients with PNS.     

Multiple paraneoplastic syndromes in a patient with antibodies to neuronal nucleoproteins (anti-Hu)

We report the clinical and autopsy studies of a patient with an unusual combination of multiple paraneoplastic neurological syndromes in association with antibodies to a 35–40 kDa neuronal nucleoprotein (anti-Hu). Neurological disease preceded the detection of a small cell carcinoma of the lung. The patient had combined sensory and motor neuronopathy or neuropathy, cerebellar degeneration, brain-stem and limbic encephalitis, and clinical evidence of the Lambert-Eaton myasthenic syndrome and gastrointestinal pseudo-obstruction of paraneoplastic origin.